The possibility that hematopoietic cell transplantation (HCT) can be used as curative therapy for patients with severe autoimmune diseases has recently become the focus of rheumatologists and HCT groups worldwide. However, little preclinical or clinical data are available that provide guidelines for how best to condition these patients for transplantation or that delineate graft compositions that will likely result in long-term cures. HCT is generally considered a high risk procedure. Our laboratory has been studying ways to make HCT safer and thus more widely available to patients with disorders other than malignancies or bone marrow failure states. In this application we plan to test high dose myeloablative, lymphoablative and attenuated non-myeloablative conditioning regimens followed by hematopoietic cell transplantation in autoimmune susceptible mice in order to determine the appropriate conditioning strategies for the treatment of human disease. Both autologous and allogeneic HCT will be studied. We will use purified hematopoietic stem cell (HSCs), alone or in combination, with other defined blood cell types to generate grafts that are optimized to restore immune function following transplantation but that do not have the capacity to reintroduce autoimmune T cells into recipients or, in the case of allogeneic transplantation, to cause graft-vs-host disease. A further goal of this application is to understand the mechanism(s) by which the proposed autologous and allogeneic HCT regimens alter immune responses to autoantigens.